Key Laboratory of Biorheological Science and Technology (Ministry of Education), Chongqing University, Chongqing, China.
College of Bioengineering, Chongqing University, Chongqing, China.
Chem Biol Drug Des. 2019 Oct;94(4):1824-1834. doi: 10.1111/cbdd.13590. Epub 2019 Aug 9.
Due to the potencies in the treatments of cancer, infectious diseases, and autoimmune diseases, the developments of human TLR8 (hTLR8) agonists and antagonists have attracted widespread attentions. The hTLR8 agonists and antagonists have similar structures but with completely opposite biological effects. Up to date, the subtle differences in the structures between the hTLR8 agonists and antagonists are still unknown. In this work, emerging chemical pattern (ECP) was successfully used to extract the key chemical patterns of the hTLR8 agonists and antagonists. By using CAEP classifier, an optimal ECP model with only 3 descriptors was established with the overall prediction accuracy larger than 90%. Further hierarchical cluster analysis and molecular docking showed that the H-bond and hydrophobic properties are the key features distinguishing the hTLR8 agonists from antagonists. Comparing with the antagonists, the agonists show stronger specific H-bond properties, while antagonists have stronger non-specific hydrophobic properties. The significant differences in the structural properties may be closely related to the activation/inhibition mechanism of hTLR8.
由于在癌症、传染病和自身免疫性疾病治疗方面的潜力，人类 TLR8（hTLR8）激动剂和拮抗剂的开发引起了广泛关注。hTLR8 激动剂和拮抗剂具有相似的结构，但具有完全相反的生物学效应。迄今为止，hTLR8 激动剂和拮抗剂之间结构上的细微差异仍不清楚。在这项工作中，新兴化学模式（ECP）成功地用于提取 hTLR8 激动剂和拮抗剂的关键化学模式。通过使用 CAEP 分类器，建立了一个仅包含 3 个描述符的最佳 ECP 模型，总体预测准确性大于 90%。进一步的层次聚类分析和分子对接表明，氢键和疏水性是区分 hTLR8 激动剂和拮抗剂的关键特征。与拮抗剂相比，激动剂表现出更强的特定氢键性质，而拮抗剂具有更强的非特异性疏水性。结构性质的显著差异可能与 hTLR8 的激活/抑制机制密切相关。
